Tobacco use is the primary preventable cause of cancer and premature death in the US and most smokers visit a healthcare setting each year, providing an unequaled opportunity to intervene. Yet, most smokers do not receive highly effective smoking treatment during their healthcare visits. To improve the effectiveness of smoking treatment in healthcare, this project will conduct a comparative effectiveness randomized clinical trial that compares two promising experimental smoking cessation treatments with one another and with usual care. The two experimental treatments are based on innovative methods: their components have all produced strong additive or interactive effects in prior experiments, they are designed to be part of a chronic care approach that addresses phase-specific challenges of smoking treatment (encountered when preparing to quit, quitting, and maintaining abstinence), and they were engineered for, and tested in, healthcare settings. Smokers (N=1200) from primary care clinics, who want to quit smoking, will be randomized to receive one of three treatments: 1) Abstinence-Optimized Treatment (to maximize cessation success): prequit nicotine gum, 26 weeks of combination nicotine patch + nicotine gum, intensive in-person counseling, and long-term phone counseling; 2) Cost-Optimized Treatment (to maximize abstinence rates for a total cost < $500): 8 weeks of combination nicotine patch + nicotine gum, intensive in-person counseling, and long-term phone counseling; or 3) Usual Care (based on the 2008 Public Health Service Guideline for cessation treatment): 8 weeks of nicotine patch, one in-person and two phone counseling sessions. Treatments will be compared on key clinical (e.g., latency to relapse) and healthcare system (e.g., net monetary benefit) outcomes, and on mechanisms thought to produce their effects. This research will, for the first time, evaluate treatments for smoking that were developed systematically and will determine their comparative effectiveness and cost-effectiveness in real-world settings. Results will be used to construct a chronic care treatment for smoking. The proposed research could shift the paradigm for treating tobacco use to a chronic care model and advance intervention science by validating new treatment development methods.